Secretion Of Atrial Natriuretic Polypeptide Research Articles

The effect of pituitary adenylate cyclase activating polypeptide on cultured rat cardiocytes as a cardioprotective factor.

In the cardiovascular system, pituitary adenylate cyclase activating polypeptide (PACAP) exhibits not only vasodilation but also positive inotropic action by increasing cardiac output. Then the effect of PACAP in cultured cardiovascular cells was examined. In neonatal rat myocytes, PACAP evoked concentration-dependent increase in intracellular cyclic AMP content more potently than vasoactive intestinal polypeptide (VIP). However, in neonatal rat nonmyocytes, PACAP and VIP showed equal potency. The characterization of the subtype of PACAP/VIP receptors by RT-PCR analysis revealed that PAC1 receptor mRNA is dominantly present in the myocytes, but VPAC2 receptor mRNA is abundant in the nonmyocytes. In the myocytes, PACAP did not change the protein synthesis stimulated by endothelin or by itself. However, PACAP moderately stimulated the secretion of atrial natriuretic polypeptide (ANP). On the other hand, PACAP inhibited the protein synthesis and DNA synthesis of the nonmyocytes. These indicate that PACAP might be involved in the regulation of cardiac hypertrophy and fibrosis as a cardioprotective factor.

The determination of vasoactive substances during autonomic dysreflexia.

Urinary bladder percussion induced autonomic dysreflexia (AD) was observed in spinal cord injured patients with a complete neurological lesion, the upper level being above T5. To document the pathology and study the etiology of autonomic dysreflexia to further investigate its mechanism, this paper presents some clinical data on the determination of vasoactive substances such as norepinephrine (NE), epinephrine (E), renin (R), angiotensin II (AII) and atrial natriuretic polypeptide (ANP) before and during bladder percussion in 30 patients with a thoracolumbar or cervical spine and spinal cord injury. It is demonstrated that tapping the urinary bladder of such patients can cause AD. Changes of some of the vasoactive substances in the plasma were also observed, which might indicate that autonomic dysreflexia result from excitation of the sympathetic nervous system. Overactivity of the sympathetic nervous system was antagonized by excitation of the vegetative nerve system. There was no correlation between changes of blood pressure and adrenal function as well as the change of R-A II system; during autonomic dysreflexia, the inclement of ANP secretion played an important role in recovering homeostasis.

Glucocorticoids potentiate the action of atrial natriuretic polypeptide in adrenalectomized rats.

Adrenal insufficiency in human and rat is associated with an impairment of the diuretic response to water load, and only glucorticoids (GCs) restore this deficit. Our observation that GCs potentiate atrial natriuretic polypeptide (ANP)-stimulated cGMP production in cultured renal cells prompted us to examine the possibility that GCs may restore the diuretic response through the potentiation of ANP action. Initially, changes in urine volume and ANP levels were studied in adrenalectomized (Adx) and sham-operated intact rats after an oral water load of 5 ml/100 g BW. Urine volume after water load was 4.5 +/- 0.5 ml/30 min in the intact rats, whereas it was 0.8 +/- 0.2 ml/30 min in the Adx rats. In the intact rats, a significant increase in plasma ANP level was observed 30 min after the water load, whereas no increase was observed in Adx rats. This defective ANP response may be involved in the impairment of the diuretic response in Adx rats. Indeed, pretreatment of Adx rats with dexamethasone (Dex, 20 micrograms/100 g BW) increased plasma ANP levels even before water load and improved diuretic response. Subsequently, effect of iv administration of human or rat ANP at a pharmacological dose (2.5 micrograms/100 g BW) on urine volume, osmolarity, and urinary excretion of cGMP, and sodium was studied in Adx rats that received an oral water load 30 min before ANP. Dex treatment was achieved by per os administration 3 h before the ANP injection. In Adx rats, the urine volume after ANP administration was 1.2 +/- 0.1 ml/30 min, and pretreatment with Dex markedly increased the urine volume to 6.3 +/- 0.4 ml/30 min. Dex also increased ANP-induced osmolar and sodium excretion by 2.6- and 2.9-fold, respectively. Although urinary excretion of cGMP was increased in Adx rats by ANP administration, a further significant increase was observed by the pretreatment with Dex. Injection of (Bu)2cGMP to Adx rats pretreated with Dex resulted in a significant increase in urine volume and osmolar and sodium excretion. However, no significant increase in urine volume was observed in Adx rats not pretreated with Dex. The present study suggests that GCs restore the diuretic response to acute water load not only by increasing the secretion of ANP but also by potentiating ANP-stimulated cGMP production. Furthermore, GCs may augment ANP action at one or more steps other than cGMP formation because administration of (Bu)2cGMP to Adx rats did not correct the diuretic response to water load.

Observations on plasma ANP levels during short-term transient myocardial ischemia produced by PTCA in patients with LAD stenosis.

Ten patients with coronary artery disease and stable angina (mean age fifty-seven) were included in the study. Five of the patients had normal left ventricular function, 5 had local hypokinesia or akinesia; 8 had one-stem and 2 had two-stem disease, but all had left anterior descending (LAD) lesions ranging from 75% to 100%. Ejection fraction varied between 35% and 75% (mean 59%). Immunoreactive atrial natriuretic polypeptide (ANP) levels in the femoral vein (FV) and the coronary sinus (CS) were measured before, immediately after, and up to twenty-four hours after percutaneous transluminal coronary angioplasty (PTCA) of the LAD. ANP secretion increased by 83% (FV) and 11% (CS) within minutes after PTCA and reached control levels after thirty to sixty minutes. In patients with hypokinesia of the anterior wall, ANP secretion was significantly lower, 48% (FV) and 11% (CS) respectively. ANP secretion during PTCA was higher in patients with concomitant increase in pulmonary capillary pressure (PCP) but was also observed without an increase of PCP, suggesting ventricular ANP secretion. IN conclusion, transient myocardial ischemia leads to immediate ANP secretion even in the absence of significant pressure elevation in the left atrium. As a part of the continuous medical education program of the American College of Angiology the second part of the paper reviews the mechanisms that allow the ischemic heart to counteract the ischemic condition and thus to escape from myocardial infarction. A review of this subject is presently not available in the literature.

Atrial natriuretic polypeptide secretion via selective activation of kappa-opioid receptor: role of dynorphin

The present study was designed to investigate the direct effect of dynorphin on atrial natriuretic polypeptide (ANP) secretion in cultured rat atrial cardiocytes via a kappa-opioid receptor activation as well as the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) system in the secretion of ANP from cardiocytes. Dynorphin stimulated ANP secretion dose and time dependently from 2-day cultured atrial cardiocytes. The dynorphin-induced ANP secretion was partially antagonized by MR2266, a selective kappa-opioid receptor antagonist. U-62066E, a selective kappa-opioid receptor agonist, stimulated ANP secretion. This stimulation was also antagonized by MR2266. However, no stimulation of ANP secretion was seen with [D-Ala2,D-Leu5]enkephalin, methionine (Met)-enkephalin, or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. Dynorphin at 10(-6) M significantly decreased the production of cAMP in the cultured cardiocytes. However, 10(-6) M Met-enkephalin had no effect on cAMP at all. The decrease in cAMP production by the addition of dynorphin was partially antagonized with a simultaneous addition of MR2266. The dynorphin-induced ANP secretion, as well as the basal secretion, were significantly decreased by the addition of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, as compared with the respective controls. Dibutyryl cAMP at 10(-3) M significantly decreased the basal secretion of ANP as compared with the control. Therefore, the present studies show that dynorphin selectively stimulates ANP secretion, at least in part, via the activation of a specific kappa-opioid receptor.

Pathophysiological Role of Augmented Atrial Natriuretic Polypeptide Gene Expression in DOCA-Salt Hypertension

To elucidate the pathophysiological significance of endogenous atrial natriuretic polypeptide (ANP) in hypertension, we investigated the biosynthesis and secretion of ANP in deoxycorticosterone acetate (DOCA)-salt hypertensive rats and also examined the effect of passive immunization with monoclonal antibody raised against alpha-rat ANP on the development of hypertension in DOCA-salt rats. The plasma ANP level in DOCA-salt rats was significantly elevated in comparison to control rats. While the atrial ANP concentration in DOCA-salt rats was not significantly altered, the atrial level of ANPmRNA in DOCA-salt rats was two-fold higher than that in control rats. These results suggest the augmented biosynthesis of ANP in the atrium and the oversecretion of ANP from the heart in DOCA-salt rats. The levels of ANP and ANPmRNA in the ventricle of DOCA-salt rats exhibited significant increases, compared with those in control rats, suggesting the induction of ANP gene expression in the ventricle of DOCA-salt hypertensive rats under pre/after overload. Weekly intravenous administrations of monoclonal antibody with high affinity for alpha-rat ANP significantly augmented the rise in blood pressure of DOCA-salt rats. These results support the hypothesis that the augmented secretion of ANP is one of the defensive mechanisms to counteract high arterial pressure in this model of hypertension.

Does atrial appendectomy aggravate secretory function of atrial natriuretic polypeptide?

The present study was designed to clarify how atrial appendectomy affects hemodynamics and secretory function of atrial natriuretic polypeptide in the failing heart. Eleven mongrel dogs were prepared for the experimental model of high-output heart failure by creation of arteriovenous fistulas between femoral arteries and veins. Two months after the first operation, effects of bilateral atrial appendectomies on basal and pacing-induced secretions of atrial natriuretic polypeptide were investigated in five dogs with simultaneous measurement of various hemodynamic indices. In the remaining six dogs, used as a control group, pacing-induced secretion of atrial natriuretic polypeptide was examined in the same way as in the appendectomy group. After excision of the atrial appendages, neither systolic blood pressure nor either atrial pressure changed, but plasma atrial natriuretic polypeptide level was decreased (292 +/- 54 to 188 +/- 47 pg/ml, p less than 0.01) and cardiac output fell (3.7 +/- 0.9 to 3.0 +/- 0.8 L/min, p less than 0.01). During pacing-induced tachycardia, the peak level of plasma atrial natriuretic polypeptide was lower in the appendectomy group than in the control groups (593 +/- 213 versus 1170 +/- 324 pg/ml, p less than 0.05), despite similar left atrial pressures in the two groups. The excised appendages contained approximately 30% of the total amount of atrial natriuretic polypeptide. These results demonstrate that atrial appendectomy decreases secretory function of atrial natriuretic polypeptide and reduces cardiac output in dogs with experimental high-output heart failure.

Hyperbaric Diuresis is Associated with Decreased Antidiuretic Hormone and Increased Atrial Natriuretic Polypeptide in Humans.

When men are exposed to a hyperbaric environment, urine flow increases. In order to elucidate the mechanism of this hyperbaric diuresis, a dry saturation dive experiment was carried out. Five male subjects were exposed to a 16-21 ATA (atmospheric pressure absolute) helium-oxygen (He-O2) environment for 4 days. Five blood samples were obtained in the early morning (0600-0630 h): once at predive 1 ATA air, 3 times at 16-21 ATA He-O2, and once at postdive 1 ATA air. Eight-hour timed urine samples, 0600-1400 h, 1400-2200 h, and 2200-0600 h (night urine), were collected throughout the experimental period. Urine flow markedly increased by the exposure to hyperbaria in the presence of constant creatinine clearance. The increase was mostly attributable to the urine flow during 2200-0600 h. The secretion of antidiuretic hormone (ADH) was suppressed at daytime and night during the exposure. On the other hand, the secretion of atrial natriuretic polypeptide (ANP) increased solely at night during hyperbaria and correlated with the increases of both the nocturnal urine flow and the nocturnal urinary excretion of sodium. These results suggest that both suppressed ADH secretion and stimulated ANP secretion cause hyperbaric diuresis.

Dynamic exercise-induced elevation in plasma levels of atrial natriuretic peptide in patients with effort angina pectoris

We investigated the relationship between plasma atrial natriuretic polypeptide (ANP) levels and hemodynamic indices during dynamic exercise testing in 15 patients with effort angina pectoris. Patients exercised on an angina-limited, supine, multistage bicycle ergometer, and plasma ANP levels and hemodynamic indices were measured at rest, at peak exercise, and 6 minutes after exercise. Plasma ANP levels increased significantly at peak exercise. Pulmonary artery wedge pressure (PAWP) and coronary sinus blood flow (CSBF) were significantly correlated with plasma ANP levels before and at peak exercise (PAWP: r = 0.69, p < 0.001; CSBF; r = 0.45, p < 0.05). In six of eight patients whose PAWP exceeded 20 mm Hg at peak exercise, plasma ANP levels were increased at 6 minutes after exercise, whereas PAWP had decreased relative to the values obtained at peak exercise. Plasma ANP concentrations at 6 minutes after exercise were not correlated with PAWP at the same time. However, PAWP at peak exercise was correlated with the plasma ANP levels at 6 minutes after exercise ( r = 0.80, p < 0.001). These results suggest that in patients with effort angina pectoris left ventricular dysfunction resulting from exercise-induced myocardial ischemia may increase preload excessively and may contribute to the excess secretion of ANP after dynamic exercise.

Atrial pacing stimulates secretion of atrial natriuretic polypeptide without elevation of atrial pressure in awake dogs with experimental complete atrioventricular block.

To clarify whether or not tachycardia stimulates the secretion of atrial natriuretic polypeptide (ANP) without elevation of atrial pressure, we examined the effects of atrial pacing on ANP secretion in awake dogs with normal sinus rhythm and with complete atrioventricular block (CAVB), which was produced surgically by heat cauterization of His' bundle. In four dogs with normal sinus rhythm, atrial pacing increased the atrial rate from 146 +/- 20 to 260 +/- 10 beats/min, with marked elevation of right atrial pressure (from 0.2 +/- 0.1 to 3.9 +/- 0.8 mm Hg) and left atrial pressure (from 0.2 +/- 0.1 to 8.6 +/- 2.8 mm Hg). Along with the hemodynamic changes, the ANP level in plasma obtained from the coronary sinus was increased from 405 +/- 99 to 849 +/- 199 pg/ml (p less than 0.01). In five dogs with CAVB, the ANP level was also significantly increased from 730 +/- 82 to 1,137 +/- 35 pg/ml (p less than 0.01) by rapid atrial pacing (from 164 +/- 20 to 317 +/- 30 beats/min) in spite of the lack of any appreciable changes in either left or right atrial pressure. Furthermore, in the CAVB group, while the ventricular rate was increased by ventricular pacing from 52 +/- 5 to 146 +/- 16 beats/min, atrial pacing was performed simultaneously without atrioventricular (A-V) sequential form. Even under this condition, the ANP level was increased from 480 +/- 172 to 626 +/- 223 pg/ml (p less than 0.05) without any substantial changes in atrial pressure. Such effects of rapid atrial pacing on ANP secretion were suppressed after infusion of autonomic blocking agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic blockade of endogenous atrial natriuretic polypeptide (ANP) by monoclonal antibody against ANP accelerates the development of hypertension in spontaneously hypertensive and deoxycorticosterone acetate-salt-hypertensive rats.

To explain the pathophysiological significance of endogenous atrial natriuretic polypeptide (ANP) in the development of hypertension, we examined the effect of chronic, repetitive administrations of MAb raised against alpha-rat ANP in two rat models of hypertension, spontaneously hypertensive rats of the stroke prone substrain (SHR-SP), and deoxycorticosterone acetate (DOCA)-salt rats. Weekly intravenous administrations of MAb with high affinity for alpha-rat ANP, named KY-ANP-II (MAb[KY-ANP-II]), started at the age of 6 wk, significantly augmented the rise in blood pressure of SHR-SP, compared with control SHR-SP treated with another MAb with quite low affinity for alpha-rat ANP, named KY-ANP-I (MAb[KY-ANP-I]), throughout the observation period. The administrations of MAb[KY-ANP-II] had no significant effect on blood pressure of age-matched normotensive Wistar Kyoto rats, compared with those receiving MAb[KY-ANP-I]. Weekly administrations of MAb[KY-ANP-II] also significantly aggravated hypertension in DOCA-salt rats. Blood pressure of DOCA-salt rats treated with MAb[KY-ANP-II] was significantly higher than that of DOCA-salt rats treated with MAb[KY-ANP-I] throughout 8 wk of DOCA and 1% saline administration. The administration of MAb[KY-ANP-II] also significantly attenuated exaggerated diuresis and natriuresis in DOCA-salt rats compared with those treated with MAb[KY-ANP-I]. Elevated plasma cGMP levels of both SHR-SP and DOCA-salt rats were significantly reduced by the administration of MAb[KY-ANP-II]. These results suggest the compensatory role of augmented secretion of ANP in these hypertensive rats and support the concept that augmented secretion of ANP could represent an antihypertensive deterrent mechanism.

Increased Synthesis and Secretion of Atrial Natriuretic Polypeptide During Viral Myocarditis

To elucidate the pathophysiological role of atrial natriuretic polypeptide (ANP) in diseased hearts, ANP levels in atrial and ventricular tissues and plasma were investigated in mice with congestive heart failure after viral myocarditis. The study was performed on day 14 after encephalomyocarditis viral inoculation, when congestive heart failure developed. The atrial ANP level increased to a value two times higher than that of noninoculated age-matched mice (the control mice). The ventricles of the control mice contained an approximately 1,000-fold lower ANP level than the atrial ANP level. The ventricular ANP concentration of the infected mice showed about a 21 times higher level than the control value. The plasma ANP level was also elevated 20 times. On immunofluorescence studies, increase of immunostaining were found in the atria of the infected mice, and positive staining appeared on the cardiocytes in almost all areas of the remaining ventricular tissues of the infected mice, whereas staining was not found on the ventricles of the control mice. The staining seemed particularly strong in the area surrounding the myocardial lesions. These results indicate that atrial and ventricular ANP synthesis and ANP secretion increase in the heart with viral myocarditis. The marked increase in the ventricular ANP level suggests that the ventricle is another important production site for circulating ANP.

Increased secretion of atrial natriuretic polypeptide in response to cardiac pacing.

Effects of cardiac pacing on secretion of atrial natriuretic polypeptide (ANP) were examined in 20 patients during cardiac catheterization under control conditions. The plasma ANP concentration in the coronary sinus (900 +/- 115 pg/ml) was significantly higher than those in the aorta (147 +/- 19 pg/ml) and the femoral vein (105 +/- 15 pg/ml) (p less than 0.001). The plasma ANP concentration was also significantly higher in the aorta than in the femoral vein (p less than 0.001). Its concentration at all three sites significantly increased during cardiac pacing (from 900 +/- 115 to 1461 +/- 218, from 147 +/- 19 to 250 +/- 36, and from 105 +/- 15 to 150 +/- 24 pg/ml, respectively). However, mean right atrial pressure and mean pulmonary capillary wedge pressure showed no significant changes between control conditions and during pacing (5 +/- 1 vs 6 +/- 1, and 8 +/- 1 vs 8 +/- 1 mmHg). Furthermore, there was no significant correlation between ANP secretion and the pressure in both atria. Thus, cardiac pacing can release ANP from the heart without increasing atrial pressure.

Increased secretion of atrial natriuretic polypeptide from the left ventricle in patients with dilated cardiomyopathy.

To examine whether atrial natriuretic polypeptide (ANP) is released from the left ventricle in patients with dilated cardiomyopathy (DCM) we measured plasma ANP level in the aortic root (Ao), the anterior interventricular vein (AIV), the great cardiac vein (GCV), and the coronary sinus (CS) in 11 patients with DCM and 18 control subjects. Plasma ANP levels in Ao, AIV, GCV, and CS were 454 +/- 360, 915 +/- 584, 1,308 +/- 926, and 1,884 +/- 1,194 pg/ml, respectively, in the patients with DCM and 108 +/- 42, 127 +/- 55, 461 +/- 224, and 682 +/- 341 pg/ml, respectively, in the control subjects. There was no significant difference in the plasma ANP levels between Ao and AIV in the control subjects. On the contrary, there was a significant (P less than 0.001) step-up in plasma ANP levels between Ao and AIV in patients with DCM. Thus, the difference in ANP levels between Ao and AIV was significantly increased in patients with DCM as compared with the control subjects (461 +/- 248 vs. 19 +/- 59 pg/ml, P less than 0.001). The difference in ANP levels between Ao and CS was also significantly increased in patients with DCM as compared with the control subjects (1,429 +/- 890 vs. 577 +/- 318 pg/ml, P less than 0.001). We conclude that ANP is released in increased amounts into the circulation from the left ventricle as well as from the heart as a whole in patients with DCM.

Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart.

To elucidate the expression of the atrial natriuretic polypeptide (ANP) gene in the ventricle of the human failing heart, we have measured ANP and ANP messenger RNA (ANPmRNA) levels in left ventricular aneurysm obtained at operation, biopsy specimens of left ventricles from dilated cardiomyopathy (DCM) and autopsy samples of old myocardial infarction (OMI) and DCM hearts, and compared the levels with those in the normal ventricle. The ANP level (mean +/- SE) was 17.5 +/- 6.9 ng/g in the normal ventricle, and increased to 660.3 +/- 122.2 ng/g in the left ventricular aneurysm tissues and to 3,138.6 +/- 1,642.1 ng/g in the biopsy specimens of the DCM ventricle. These levels were approximately 40 and 200 times higher than in the normal ventricle. The increase of ANP levels was observed in both infarcted and noninfarcted regions of the OMI heart, and in the entire ventricle of the DCM heart. A significant positive correlation was found between the ANP level in aneurysm tissues and pulmonary capillary wedge pressure (r = 0.85). The ANPmRNA level in the left ventricular aneurysm showed about a 10-fold increase compared with that in the normal heart and reached 23% of that in the atrium of the same heart. A similar increase in the ANPmRNA level was observed in the entire ventricle of DCM. These data clearly indicate that the expression of the ANP gene in the ventricle is augmented in the failing heart in accordance with the severity of heart failure. In the atrium of the failing heart, ANP and ANPmRNA levels were only two times higher than those in the normal atrium. Thus, the augmentation in the expression of the ANP gene was more prominent in the ventricle than in the atrium. Taking tissue weight into account, the total content of ANPmRNA in the ventricle of the failing heart is much the same as that in the normal atrium. The ratio of the ANP level to the ANPmRNA level in the ventricle is much smaller than that in the atrium. These results suggest more rapid secretion of ANP after synthesis in the ventricle. These findings demonstrate that the expression of the ANP gene is augmented in the human ventricle of the failing heart and suggest that the ventricle becomes a substantial source of circulating ANP in congestive heart failure.

Exaggerated secretion of atrial natriuretic polypeptide during dynamic exercise in patients with essential hypertension

The plasma concentration of atrial natriuretic polypeptide (ANP) was measured in nine patients with essential hypertension during two grades of exercise tests performed in the supine position on a bicycle ergometer. The plasma ANP concentration significantly increased from 97.0 ± 19.2 pg/ml to 107.6 ± 23.7 pg/ml ( p < 0.05) during low-grade exercise (50% of the maximal heart rate) and from 96.2 ± 16.5 pg to 192.8 ± 30.7 pg/ml ( p < 0.01) during high-grade exercise (75% of the maximal heart rate). During high-grade exercise plasma epinephrine and norepinephrine concentrations showed significant increases. The plasma ANP concentration was significantly correlated with systolic blood pressure ( r = 0.51; p < 0.05). Patients with essential hypertension showed greater absolute increases in the plasma ANP concentration and systolic blood pressure during exercise compared to normotensive subjects. These results suggest that exercise stimulates secretion of ANP in response to its intensity in patients with essential hypertension and that a greater rise in atrial pressure, resulting from a greater elevation of systolic blood pressure, may be involved in the exaggerated secretion of ANP in patients with essential hypertension.

Synthesis of atrial natriuretic polypeptide in human failing hearts. Evidence for altered processing of atrial natriuretic polypeptide precursor and augmented synthesis of beta-human ANP.

To elucidate the synthesis of atrial natriuretic polypeptide (ANP) in the failing heart, 20 human right auricles obtained at cardiovascular surgery were studied. The concentration of alpha-human ANP-like immunoreactivity (alpha-hANP-LI) in human right auricles ranged from 13.8 to 593.5 micrograms/g, and the tissue alpha-hANP-LI concentration in severe congestive heart failure (CHF) (New York Heart Association [NYHA] functional class III and class IV) (235.4 +/- 57.2 micrograms/g) was much higher than that in mild CHF (NYHA class I and class II) (52.5 +/- 15.6 micrograms/g). Atrial alpha-hANP-LI levels were significantly correlated with plasma concentrations of alpha-hANP-LI in these patients (r = 0.84, P less than 0.01). High performance gel permeation chromatography and reverse phase high performance liquid chromatography coupled with radioimmunoassay for ANP revealed that the alpha-hANP-LI in the human auricle consisted of three major components of ANP, gamma-human ANP (gamma-hANP), beta-human ANP (beta-hANP) and alpha-human ANP (alpha-hANP). Comparing percentages of gamma-hANP, beta-hANP, and alpha-hANP in alpha-hANP-LI in severe CHF with those in mild CHF, the predominant component of alpha-hANP-LI was gamma-hANP in mild CHF, whereas beta-hANP and/or alpha-hANP were prevailing in severe CHF and, especially, beta-hANP was markedly increased in human failing hearts. These results demonstrate that the total ANP concentration in the atrium of the human heart is increased in severe CHF and that the increase of ANP in the human failing heart is mainly due to the increase of small molecular weight forms of ANP, beta-hANP, and alpha-hANP, especially beta-hANP, and indicate that the processing of ANP precursor, or gamma-hANP, in the human failing heart differs from that in the normal heart, suggesting that the failing heart augments synthesis and secretion of ANP as one of its own compensatory responses.

Increased Synthesis and Secretion of Atrial Natriuretic Polypeptide During Viral Myocarditis

To elucidate the pathophysiological role of atrial natriuretic polypeptide (ANP) in diseased hearts, ANP levels in atrial and ventricular tissues and plasma were investigated in mice with congestive heart failure after viral myocarditis. The study was performed on day 14 after encephalomyocarditis viral inoculation, when congestive heart failure developed. The atrial ANP level increased to a value two times higher than that of noninoculated age-matched mice (the control mice). The ventricles of the control mice contained an approximately 1,000-fold lower ANP level than the atrial ANP level. The ventricular ANP concentration of the infected mice showed about a 21 times higher level than the control value. The plasma ANP level was also elevated 20 times. On immunofluorescence studies, increase of immunostaining were found in the atrial of the infected mice, and positive staining appeared on the cardiocytes in almost all areas of the remaining ventricular tissues of the infected mice, whereas staining was not found on the ventricles of the control mice. The staining seemed particularly strong in the area surrounding the myocardial lesions. These results indicate that atrial and ventricular ANP synthesis and ANP secretion increase in the heart with viral myocarditis. The marked increase in the ventricular ANP level suggests that the ventricle is another important production site for circulating ANP.

Central interaction of the brain atrial natriuretic polypeptide (ANP) system and the brain renin-angiotensin system in ANP secretion from heart--evidence for possible brain-heart axis.

To elucidate the involvement of the brain renin-angiotensin system and the brain atrial natriuretic polypeptide (ANP) system in the regulation of ANP secretion from the heart, the effects of intracerebroventricular administration of angiotensin II and ANP on the plasma ANP level were examined in conscious unrestrained rats. The intracerebroventricular administration of angiotensin II at doses of 100 ng and 1 microgram significantly enhanced ANP secretion induced by volume-loading with 3-mL saline infusion (peak values of the plasma ANP level: control, 220 +/- 57 pg/mL; 100 ng angiotensin II, 1110 +/- 320 pg/mL, p less than 0.01; 1 microgram angiotensin II, 1055 +/- 60 pg/mL, p less than 0.01). The intracerebroventricular injection of angiotensin II at the same doses alone had no significant effect on the basal plasma ANP level. The enhancing effect of central angiotensin II on ANP secretion induced by volume-loading was significantly attenuated by pretreatment with the intravenous administration of the V1-receptor antagonist of vasopressin or with the intracerebroventricular administration of phentolamine. The intracerebroventricular administration of alpha-rANP(4-28) (5 micrograms) had no significant influence on the basal plasma ANP level; however, it significantly attenuated central angiotensin II potentiating effect of volume-loading induced ANP secretion. These results indicate that the brain renin-angiotensin system regulates ANP secretion via the stimulation of vasopressin secretion and (or) via the activation of the central alpha-adrenergic neural pathway, and that the brain ANP system interacts with the brain renin-angiotensin system in the central modulation of ANP secretion from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased Synthesis and Secretion of Atrial Natriuretic Polypeptide (ANP) in the Left Atrium of Spontaneously Hypertensive Rats (SHR)

Increased Synthesis and Secretion of Atrial Natriuretic Polypeptide (ANP) in the Left Atrium of Spontaneously Hypertensive Rats (SHR)